This application proposes the first test of a novel therapeutic model, in which a pro-cognitive agent augments the impact of a cognitive therapy for schizophrenia (SZ). Pharmacologic Augmentation of Cognitive Therapy (PACT) for SZ, first proposed by the PI in 2010 and first tested in this application, funda- mentally challenges existing approaches to enhancing function in SZ patients, both in theory and practice. To date, MH59803 has investigated the neural regulation of laboratory-based measures of deficient information processing in SZ patients, using preclinical rodent and healthy human models to explicate the biology of these deficits, and to establish a rational basis for developing novel therapies for SZ. MH59803 studies of the neural regulation of prepulse inhibition (PPI) of startle in rats initially probed basic anatomical, neurochemical and molecular mechanisms. These studies then moved from bench-to-bedside, focusing on dopamine (DA) agonist effects on PPI and neurocognition in healthy human subjects (HS), and their regulation by genes identified in cross-species studies. In the process, MH59803 detected biomarkers that predict PPI- enhancing and pro-cognitive effects of the DA releaser, amphetamine (AMPH). These findings have led to specific predictions of AMPH effects on PPI and neurocognition in antipsychotic (AP)-medicated SZ patients that, if confirmed in the present application, could help transform therapeutic approaches to SZ. This renewal application reflects a logical progression of studies at systems and molecular levels, translated next to HS, and now to experimental models in SZ patients. The path of bench-to-bedside progress in MH59803 has helped generate a critical paradigm shift in therapeutic models for SZ, which will directly address the need for more effective treatments for this devastating disorder. In Aim 1, the effects of AMPH (placebo (PBO) vs. 10, or PBO vs. 20 mg, p.o.) will be tested on PPI, neurocognition (assessed with the MATRICS Consensus Cognitive Battery (MCCB)) and computerized Targeted Cognitive Training (TCT) performance in 120 AP-treated SZ patients and 40 HS, in a double-blind, randomized, PBO-controlled cross-over design. Moderating roles on AMPH effects will be assessed for both behavioral (low baseline performance) and genetic (single nucleotide polymorphisms for catechol-O-methyl- transferase (COMT)) biomarkers. In Aim 2, parallel animal model studies will inform Aim 1 results in AP- medicated SZ patients by testing the effects of systemic APs and D1 antagonism on: 1) AMPH-potentiated PPI, and 2) AMPH effects on new cross-species paradigms assessing MCCB-like measures of a 5-choice continuous performance task and a TCT-like sensory discrimination task in rats. In total, Aim 1 findings will generate strong, testable predictions about the ability of AMPH to safely enhance the benefits of cognitive therapies in biomarker-identified SZ patients; Aim 2 will establish informative animal models to explicate the neural basis of Aim 1 findings, setting the stage for future advances in this novel approach to SZ therapeutics.